Proper medical treatment of pain remains a challenge for patients and healthcare professionals. Optimal pharmacologic management of pain requires selection of analgesic drugs that achieve rapid efficacy with minimal side effects. Traditionally, opioid analgesics have provided the most important options for pain treatment. However, misuse and abuse of opioids are widespread social and medical problems that may deter physicians from prescribing these useful drugs.
In addition, accidental and intentional overdose with prescription and/or over-the-counter (OTC) drugs is a serious health problem that is associated with thousands of fatalities every year. Opioid overdose is a significant and growing problem associated with drug abuse, but overdoses also occur accidentally (e.g., when a child obtains and ingests an opioid drug, say Oxycontin® or Opana® or Vicodin®), or intentionally (e.g., when related to suicide attempts). Accidental overdose can also commonly occur when unusually potent batches of illicit opioids are ingested by drug addicts or other abusers.
Opioid abuse is an increasing problem, and opioids have become one of the most widely abused drugs. The opioid drug is also known as “a poor man's heroin” because of its comparatively lower street price. Moreover, crushing and snorting intranasally the delayed release form of oxycodone (known by the brand name as Oxycontin®), results in rapid drug release and absorption, which results in high peak blood concentrations that produce a quick “high” but can also precipitate a fatal overdose (Aquina et al (2009) Post Graduate Medicine 121: 163-167). Necrosis of intranasal structures, similar to the damage associated with cocaine use, is also a consequence of prolonged Oxycontin® abuse by snorting crushed tablets. Moreover, crushing and intranasally snorting the extended release form of oxymorphone (known by the brand name as Opana-ER®), results in rapid drug release and absorption, causing high peak blood concentrations that produce a quick “high” but can also precipitate a fatal overdose. Moreover, in March 2015, Austin, Ind. was the center of an HIV outbreak caused by the use of opioids as an injectable recreational drug. Opioids such as Opana® have various street names, such as “blues”, “moons”, “blue heaven”, “pink lady”, “Mrs. O”, and others.
A further shortcoming of many opioids is their generally low oral bioavailability. Poor oral bioavailability results in variable blood levels, and consequently variable patient response—a highly undesirable feature in the treatment of pain where rapid and reliable relief is critical.
Researchers and the pharmaceutical industry have sought to prevent the potential harmful effects of opioid overdose by creation of various drug formulations. For example, opioids have been combined with opioid antagonists. Such formulations are designed to counteract an oral opioid if the formulation is disrupted (e.g., crushed) prior to oral administration, or if the drug is taken administered parenterally (e.g., injected intravenously). To cite an example of a non-opioid drug with known abuse potential, extended-release methylphenidate (Concerta®) has been formulated in a paste that can preclude administration by snorting or injection. Another example is the drug Embeda® where the opioid drug morphine is co-formulated with the antagonist naltrexone in sequestered fashion. Other compositions have been coated with emetic agents in quantities that—if administered in moderation as intended—no emesis occurs; however, if excessive amounts are ingested, emesis is induced to prevent overdose. However, such methods, as well as conventional controlled-release formulations, are often ineffective and can be circumvented.
In addition to oxymorphone hydrochloride, oxymorphone is also an ingredient of Opana® Injection (injectable), Opana® ER (extended-release tablet), Opana® IR (immediate-release tablet), Numorphan® (suppository and injectable solution), and O-Morphon® (both tablet and injectable). It is a semi synthetic narcotic analgesic derived from thebaine. Typical adult doses of opioid range from 5-40 mg as the oral hydrochloride salt, whereas the injectable adult dose is approximately 1 mg as the hydrochloride salt, with a dosing interval ranging from 4-12 hours.
In addition to Oxycontin®, oxycodone is also an ingredient of well-known drugs such as Percodan®, Percocet®, Roxicet®, and Tylox®. As a semi-synthetic narcotic derived from thebaine, oxycodone is also available in oral formulations combined with aspirin, phenacetin, and caffeine. A typical adult dose of oxycodone is 2.5-5 mg administered orally as the hydrochloride or terephthalate salt every 6 hours. While typically used for the relief of moderate to moderately severe pain, opioid can also produce drug dependence of the morphine type.
In the case of hydrocodone, there are several FDA approved products in the market, but most of them are combination products, mainly co-formulated with acetaminophen. In addition to Vicodin®, hydrocodone is also an ingredient of well-known drugs such as Hy-Phen®, Co-Gesic®, Hycodan®, Codamine®, Hysingla®, Lortab®, Lorcet-HD®, Norcet®, Vicoprin®, Zohydro ER®, Zydone® etc. to mention a few.
Various types of prodrugs have been proposed to improve the oral bioavailability of opioids. These have included simple ester conjugates that are subject to hydrolysis by plasma esterases. Moreover, the rapidity of ester hydrolysis within the gut or through first-pass metabolism in the liver has further limited the utility of this approach. More sophisticated ester-conjugated opioid prodrugs have been synthesized. However, in the 20 years since ester conjugates were first reported, no such prodrugs have been approved as marketed products, which suggests that this approach has not been successful.
Consequently, improved methods are urgently needed to make pharmaceutically effective opioid compounds, along with compositions and methods of using such compounds, to reduce the potential for overdose and to reduce or deter opioid substance abuse while maintaining intended analgesic utility. Potentially useful compounds may also prevent—or substantially diminish or delay—uptake into the brain if the compounds were administered by routes other than approved oral administration.
Ideally, a prodrug moiety and its linkage to a particular opioid would be cleaved at an appropriate rate and site, which would then release the active opioid compound into the blood and provide the intended analgesic benefit. There remains a critical need for the treatment of severe pain with opioids using products that retain all their pharmacological advantages but sharply reduce their principal limitations, including adverse gastrointestinal effects (e.g., constipation), variable bioavailability after oral dosing, opioid overdose, and misuse, illegal/illicit use and product tampering.